Quality agreements are a crucial element in the relationship between a sponsor company and contract service provider. Recent draft guidance from FDA on contract manufacturing and quality agreements highlights the importance of such agreements and define the roles and responsibilities of each party to be in keeping with quality risk-management principles.

The expectations between a sponsor company and contract service provider define not only the nature of the outsourced relationship but also dictate the quality of the material being supplied or service provided. Quality agreements between contract manufacturers and their pharmaceutical customers are a well-established practice. Recent draft guidance by FDA brings quality agreements into greater focus by applying the science- and risk-based approach inherent in quality risk-management principles and practices.

Defining responsibilities FDA issued its draft guidance, Contract Manufacturing Arrangements for Drugs: Quality Agreements, in May 2013 to describe the agency’s current thinking on defining, establishing, and documenting the responsibilities of parties involved in contract cGMP manufacturing of drugs (1). Public comment on the draft guidance was scheduled to close at the end of July 2013 (1). The draft guidance describes how parties involved in contract manufacturing of drugs can use quality agreements to delineate their responsibilities and ensure drug quality, safety, and efficacy. The guidance applies to the commercial manufacturing of APIs (drug substances or their intermediates), finished drug products, combination products, and biological drug products (1).

Defining the roles and responsibilities of each party (i.e., sponsor company and contract manufacturer) is crucial to a quality agreement. For purposes of the draft guidance, the “owner” is defined as the party that introduces the drug into interstate commerce, whether the drug is covered by a marketing application/license or not. The “contracted facilities” are the outside entities performing manufacturing operations for the product owner. Some of the manufacturing operations performed by contracted facilities include: formulation, fill–finish, chemical synthesis, cell-culture manufacturing and fermentation for biological products, analytical testing, other laboratory services, and packaging and labeling. The draft guidance specifies that the owner is responsible for ensuring that drugs introduced for interstate commerce are neither adulterated nor misbranded as a result of the actions of their selected contracted facilities. In turn, all contracted facilities must ensure compliance with applicable cGMP for all manufacturing, testing, or other support operations performed to make a drug(s) for the owner (1).

The quality agreements described under the draft guidance fit within the larger scheme of pharmaceutical quality systems and provisions of ICH guidelines, including ICH Q7 Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients, ICH Q9 Quality Risk Management, and ICH Q10 Pharmaceutical Quality Systems (1–4). In the draft guidance, FDA specifies that the principles of quality management extend to contract manufacturing, and that the agency FDA expects parties engaged in contract manufacturing to implement quality-management practices. The draft guidance is intended to build upon the quality-management principles in ICH guidelines in developing and executing contracted-manufacturing arrangements (1-4).

ICH Q7, for example, recommends that manufacturers evaluate contractors for cGMP compliance by establishing a formal agreement that delineates cGMP responsibilities, including quality measures and also by auditing the contractor’s facilities. Product owners may hire another party to perform the operational processes that are part of a manufacturer’s inherent responsibilities, and quality systems call for quality agreements (i.e., contracts) that clearly describe the materials or service, quality specification responsibilities, and communication mechanisms.

ICH Q10 specifies that quality risk management include certain key activities. For example, the guideline specifies that before outsourcing manufacturing activities, the owner should conduct a risk review that evaluates the extent of controls required for the particular supplier and the particular product or service covered by the agreement. Based on this risk, the owner should assess the appropriate oversight and assess the suitability and competence of the potential contracted facility to carry out the activity (e.g., audits, material evaluations, and qualification). Additionally, owners and contracted facilities should define the responsibilities and communication processes for quality-related activities of the involved parties, and document these in a written agreement between the owner and contracted facility. Owners also should monitor and review the performance of the contracted facility and identify and implement any needed improvements.Additionally, all parties performing manufacturing operations should monitor incoming ingredients and materials to ensure they are from approved sources using the agreed supply chain (1-4).

The draft guidance notes that although written quality agreements are not explicitly required under existing cGMP, owners and contracted facilities can draw on these quality-management principles to carry out the complicated process of contract drug manufacturing by defining, establishing, and documenting the responsibilities of all parties involved in drug manufacturing, testing, or other support operations. Accordingly, FDA recommends that owners and contracted facilities implement written quality agreements as a tool to delineate responsibilities to ensure the quality, safety, and effectiveness of drug products (1).